Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Review: Tacrine has limited efficacy for Alzheimer disease

ACP J Club. 1998 Mar-April; 128:46. doi:10.7326/ACPJC-1998-128-2-046


Source Citation

Glennie J, for the Canadian Coordinating Office for Health Technology Assessment (CCOHTA). The efficacy of tacrine and the measurement of outcomes in Alzheimer's Disease. CCOHTA Technology Overview: Pharmaceuticals. 1997 Jul; Issue 5.


Abstract

Objective

To evaluate the efficacy of tacrine on cognition, functioning, and behavior in patients with Alzheimer disease.

Data sources

This review is based on data reported in a separate study commissioned by the CCOHTA.* Studies published in English or French were identified from a literature search (1990 on) and 3 unpublished sources.

Study selection

Randomized controlled trials that studied the effects of tacrine on cognitive and functional outcomes in patients with Alzheimer disease and met criteria for scientific quality were selected. Cost studies were also retrieved.

Data extraction

Data were extracted on study design and methods; sample size and follow-up; and measures of cognition (Mini Mental State Examination, Alzheimer Disease Assessment Scale-cognitive, Cambridge Mental Disorders of the Elderly Examination-cognitive, and Abbreviated Mental Test Score), functioning (Progressive Deterioration Scale, Instrumental Activities of Daily Living Scale, Rapid Disability Rating Scale, and Functional Life Scale), and behavior.

Main results

10 randomized controlled trials (5 crossover and 5 parallel designs) involving 2136 patients (range 12 to 650) met the selection criteria. Meta-analysis was not done because of variations in dose, treatment duration, and outcome measures. 4 studies (3 parallel, 1 crossover) reported varying degrees of improved cognitive outcomes with tacrine, and 6 studies found no difference. 1 study found an improvement in functioning. Withdrawal rates caused by adverse effects ranged from 18% to 25%. Hepatotoxicity occurred in 12% to 64% of patients; autonomic or cholinergic adverse effects were mainly gastrointestinal and occurred in 72% to 92% of patients. 1 cost study showed that use of tacrine was associated with a 17% reduction in cost over that which would have been incurred without tacrine.

Conclusions

Tacrine has a small, clinically unimportant effect on cognition for patients with mild to moderate Alzheimer disease; no improvement in functioning is seen. Any beneficial effect may be outweighed by side effects.

Sources of funding: The federal, provincial, and territorial governments of Canada.

For article reprint: CCOHTA Publications, 110-955 Green Valley Crescent, Ottawa, Ontario K2C 3V4, Canada. FAX 613-226-5392.

*Wolfson C, Moride Y, Perrault A, Vida S. A study of the efficacy, effectiveness and economic impact of tacrine in Alzheimer's Disease. Ottawa, Ontario: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); 1997.


Commentary

It is unusual for this journal to review a position paper from a public agency, but the assessment by Glennie highlights important controversies in determining the effectiveness of disease-modifying therapy for Alzheimer disease. The conclusion that tacrine's unpredictable and modest potential effectiveness may be offset by the high risk for side effects leaves little justification for prescribing it, given the availability of a safer and efficacious alternative—donepezil.

Equally important to the clinician is the conclusion that the technology used to evaluate the efficacy of tacrine has serious methodologic flaws. The outcome measures used in the main tacrine trials, and in the clinical trial used to gain U.S. Food and Drug Administration approval for donepezil, lack proven validity and reliability (Clinician's Global Impression of Change), sensitivity to change (Mini Mental State Examination), or clinical relevance (Alzheimer Disease Assessment Scale-cognitive), and most are unsuitable for the clinical setting. As well, no standardized method exists to evaluate the effectiveness of treatment for Alzheimer disease in individual patients.

Behavior, social functioning, and activities of daily living are more meaningful to clinicians and families than performance on cognitive tests. When relevant outcomes, such as time to nursing home placement or number of problem behaviors are chosen, tacrine shows additional benefits (1, 2), which are also likely to be found with the newer, less toxic, cholinesterase inhibitors. New research instruments developed to improve the evaluation of behavior, functioning, and global change (3) should be adaptable into efficient, office-based tools. Clinicians should routinely inquire about the activities of daily living, social functioning, and behaviors of their patients with dementia, regardless of whether they are receiving treatment for Alzheimer disease.

Calvin H. Hirsh, MD
University of California, DavisSacramento, California, USA

Calvin H. Hirsh, MD
University of California, Davis
Sacramento, California, USA


References

1. Knopman D, Schneider L, Davis K, et al. Long-term tacrine (Cognex) treatment: effects on nursing home placement and mortality, Tacrine Study Group. Neurology. 1996;47: 166-77.

2. Kaufer DI, Cummings JL, Christine D. Effect of tacrine on behavioral symptoms in Alzheimer's disease: an open-label study. J Geriatr Psychiatry Neurol. 1996;9:1-6.

3. Ferris SH, Mackell JA, Mohs R, et al. A multicenter evaluation of new treatment efficacy instruments for Alzheimer's disease clinical trials: overview and general results. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11(Suppl 2): S1-12.